Biomedical subjects

B D Hegarty

Publications and source records attributed to B D Hegarty.

6 recordsLinked to original sources

PubMed2005

Long chain fatty acyl-CoA synthetase 5 expression is induced by insulin and glucose: involvement of sterol regulatory element-binding protein-1c.

In a screen for sterol regulatory element-binding protein (SREBP)-1c target genes in the liver, we identified long chain fatty acyl-CoA synthetase 5 (ACS-5). Hepatic ACS-5 mRNA is poorly expressed during fasting and diabetes and strongly induced by carbohydrate refeeding and insulin treatment. In cultured hepatocytes, insulin and a high glucose concentration induce ACS-5 mRNA. Adenoviral overexpression of a nuclear form of SREBP-1c in liver of diabetic mice or in cultured hepatocytes mimics the effect of insulin to induce ACS-5. By contrast, a dominant negative form of SREBP-1c abolishes the effect of insulin on ACS-5 expression. The dietary and SREBP-1c-mediated insulin regulation of ACS-5 expression indicate that ACS-5 is involved in the anabolic fate of fatty acids.

Animals↗

PubMed2004

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin.

AIMS/HYPOTHESIS: Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [(3)H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion. METHODS: Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours. RESULTS: Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake. CONCLUSIONS/INTERPRETATION: These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.

Animals↗

PubMed2003

The role of intramuscular lipid in insulin resistance.

There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.

Acyl Coenzyme A↗

PubMed2001

Effects of gestation on ovine fetal and maternal angiotensin receptor subtypes in the heart and major blood vessels.

Previous studies in fetal sheep have concluded that (a) the vascular AT(1) angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT(1) specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT(1) receptors first appear. We measured AT(1) and AT(2) receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term approximately 150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT(1) and AT(2) receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT(2) receptors were found. The proportion of carotid artery and aortic AT(1) receptors increased with age, while the proportion of AT(2) receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT(1) receptors. The highest density of Ang II receptors was found in the fetal heart where the AT(2) subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT(2) subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT(1) receptors, and we have documented for the first time that the appearance of AT(1) receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT(1) receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels. Experimental Physiology (2001) 86.1, 71-82.

Aging↗

PubMed2000

Effect of cortisol on fetal ovine vascular angiotensin II receptors and contractility.

The renin angiotensin system is important in the regulation of fetal blood pressure. This study investigated the expression of angiotensin AT(1) and AT(2) receptors in the ovine fetal heart, aorta and umbilical artery, and how these receptors are affected by cortisol. Cortisol infusion into the fetus has previously been shown to cause an increase in fetal blood pressure. We hypothesised that this effect of cortisol is mediated by upregulation of the angiotensin AT(1) receptor. Binding studies performed on tissues with intact endothelium demonstrated both receptor subtypes in the fetal aorta and right ventricle, although the latter contained mainly angiotensin AT(2) receptors. In contrast, only angiotensin AT(1) receptors were found in the umbilical artery. Cortisol infusion into fetuses (3 mg/day for 3-5 days) caused a physiological increase in plasma cortisol levels to 29+/-4 nM. This was associated with an increase in systolic pressure (57.8+/-1.7 vs. 52.2+/-1.5 mm Hg, P<0.05), but cortisol had no effect on the density or affinity of angiotensin receptors, nor on the in vitro contractile responses of carotid and umbilical arterial rings to 5-microM angiotensin II. In conclusion, this study has demonstrated differential expression of angiotensin AT(1) and AT(2) receptors in the different regions of the ovine fetal cardiovascular system and that the angiotensin AT(1) receptor is functional. The lack of any effect of low doses of cortisol on these receptors and on the contractility of isolated fetal vessels to angiotensin II suggests cortisol acts by other mechanisms to raise fetal arterial pressure.

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed2000

Local factors modulate tissue-specific NEFA utilization: assessment in rats using 3H-(R)-2-bromopalmitate.

Insulin-resistant states are associated with accumulation of muscle lipid, suggesting an imbalance between lipid uptake and oxidation. We have employed a new fatty-acid tracer [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP) to study individual-tissue nonesterified fatty acid (NEFA) uptake in states with diminished or enhanced lipid oxidation. 3H-R-BrP was administered to conscious male Wistar rats (approximately 300 g) during fasting (5, 18, or 36 h), acute blockade of beta-oxidation (etomoxir, 15 micromol/kg), and insulin infusion (0.25 U x kg(-1) x h(-1)). Estimates of NEFA clearance rates (K(f)*) and absolute rates of uptake (R(f)*) were calculated from tissue accumulation of 3H-R-BrP products. In the basal state, NEFA uptake was dependent on the oxidative capacity of tissues: R(f)* in brown adipose tissue (BAT) > heart (HRT) > diaphragm (DPHM) > red quadriceps (RQ) > white quadriceps (WQ) > white adipose tissue (WAT). Fasting increased (P < 0.001) K(f)* in WAT but did not change NEFA clearance in other tissues. However, plasma NEFA levels were raised (P < 0.01), tending to elevate R(f)* in most tissues (P < 0.05: WAT, BAT, WQ, DPHM). Etomoxir reduced (P < 0.01) K(f)* only in oxidative tissues (BAT, RQ, DPHM, HRT). Insulin lowered plasma NEFA levels (P < 0.001) and significantly decreased R(f)* in most tissues (P < 0.05: WAT, RQ, DPHM, HRT). An increased (P < 0.05) clearance was observed in WAT, BAT, and WQ; a decrease (P < 0.01) in K(f)* was observed in HRT. This study is the first to measure tissue-specific NEFA uptake in conscious rats in the postabsorptive, fasted, and insulin-stimulated states. We have demonstrated that tissue NEFA utilization is not exclusively determined by systemic availability, but that the early steps of NEFA uptake or metabolic sequestration can also be rapidly modulated by local processes such as NEFA oxidation.

Adipose Tissue↗